LPS (lipopolysaccharide) is a major integral structural component of the outer membrane of Gram-negative bacteria and activates monocytes and macrophages to produce cytokines such as TNF-α [Young, L R, et al., (2006) Lung-restricted macrophage activation in the pearl mouse model of Hermansky-Pudlak syndrome. J Immunol 176:4361-4368]. LPS stimulates intracellular signaling pathways by regulating activation of cytoplasmic signaling proteins including tyrosine kinases [Zanin-Zhorov, A, et al., (2007) Cutting edge: T cells respond to lipopolysaccharide innately via TLR4 signaling. J Immunol 179:41-44; Khadaroo, R G, et al., (2003) Oxidative stress reprograms lipopolysaccharide signaling via Src kinase-dependent pathway in RAW 264.7 macrophage cell line. J Biol Chem 278:47834-47841] leading to activation of mitogen-activated protein kinase (MAPK), such as p38 MAPK and c-jun-N-terminal kinase (JNK), which is involved in synthesis of certain cytokines [Lin, W N, et al., (2007) Involvement of MAPKs and NF-kappaB in LPS-induced VCAM-1 expression in human tracheal smooth muscle cells. Cell Signal 19:1258-1267; Handley M E, et al., (2005) JNK activation limits dendritic cell maturation in response to reactive oxygen species by the induction of apoptosis. Free Radic Biol Med 38:1637-1652]. The transcription factor (LITAF) that associates with STAT6B and plays a major role in transcription of several inflammatory cytokines including TNF-α [Tang, X, et al., (2005) Identification and functional characterization of a novel binding site on TNF-alpha promoter. Proc Natl Acad Sci USA 100:4096-4101; Tang, X, et al., (2003) LPS induces the interaction of a transcription factor, LPS-induced TNF-alpha factor, and STAT6(B) with effects on multiple cytokines. Proc Natl Acad Sci USA 102:5132-5137]. Although the mechanism by which it regulates expression of LITAF is not fully investigated, activation of p38 MAPK is required for LITAF gene expression in response to LPS stimulation [Tang, X, et al., (2006) LPS-induced TNF-alpha factor (LITAF)-deficient mice express reduced LPS-induced cytokine: Evidence for LITAF-dependent LPS signaling pathways. Proc Natl Acad Sci USA 103:13777-13782].
LPS and other compounds are instrumental in inflicting disease and discomfort by stimulating inflammatory reactions. Some such reactions, such as toxic shock syndrome, can be fatal. Although the pathways leading to such outcomes are not totally understood, there is still a need for addressing the treatment of diseases caused by inflammatory responses.
Therefore, what is needed is novel compositions and methods for the treatment of inflammatory diseases.